The Clinical Pharmacogenetics Implementation Consortium Guideline for SLCO1B1, ABCG2, and CYP2C9 genotypes and Statin-Associated Musculoskeletal Symptoms

Rhonda M Cooper-DeHoff^{1

2}, Mikko Niemi^{3

4

5}, Laura B Ramsey^{6

7}, Jasmine A Luzum⁸, E Katriina Tarkiainen^{3

4

5}, Robert J Straka⁹, Li Gong¹⁰, Sony Tuteja¹¹, Russell A Wilke¹², Mia Wadelius¹³, Eric A Larson¹², Dan M Roden^{14

15}, Teri E Klein¹⁰, Sook Wah Yee¹⁶, Ronald M Krauss¹⁷, Richard M Turner¹⁸, Latha Palaniappan¹⁹, Andrea Gaedigk²⁰, Kathleen M Giacomini¹⁶, Kelly E Caudle²¹, Deepak Voora²²

Affiliations

¹ Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics and Precision Medicine, College of Pharmacy, University of Florida, Gainesville, Florida, USA.
² Division of Cardiovascular Medicine, Department of Medicine, College of Medicine, University of Florida, Gainesville, Florida, USA.
³ Department of Clinical Pharmacology, Individualized Drug Therapy Research Program, University of Helsinki, Helsinki, Finland.
⁴ HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland.
⁵ Individualized Drug Therapy Research Program, University of Helsinki, Helsinki, Finland.
⁶ Divisions of Clinical Pharmacology & Research in Patient Services, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
⁷ Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
⁸ Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, Michigan, USA.
⁹ Department of Experimental and Clinical Pharmacology, University of Minnesota College of Pharmacy, Minneapolis, Minnesota, USA.
¹⁰ Department of Biomedical Data Science, School of Medicine, Stanford University, Stanford, California, USA.
¹¹ Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
¹² Department of Internal Medicine, University of South Dakota Sanford School of Medicine, Sioux Falls, South Dakota, USA.
¹³ Department of Medical Sciences, Clinical Pharmacogenomics & Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
¹⁴ Division of Cardiovascular Medicine and Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
¹⁵ Department of Pharmacology and Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
¹⁶ Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, USA.
¹⁷ Departments of Pediatrics and Medicine, University of California, San Francisco, California, USA.
¹⁸ The Wolfson Centre for Personalised Medicine, University of Liverpool, Liverpool, UK.
¹⁹ Division of Primary Care and Population Health, Stanford University School of Medicine, Stanford, California, USA.
²⁰ Division of Clinical Pharmacology, Toxicology, and Therapeutic Innovation, Children's Mercy Kansas City and School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri, USA.
²¹ Division of Pharmaceutical Sciences, Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
²² Department of Medicine, Duke Center for Applied Genomics & Precision Medicine, Duke University School of Medicine, Durham, North Carolina, USA.

PMID: 35152405
PMCID: PMC9035072
DOI: 10.1002/cpt.2557

Practice Guideline

The Clinical Pharmacogenetics Implementation Consortium Guideline for SLCO1B1, ABCG2, and CYP2C9 genotypes and Statin-Associated Musculoskeletal Symptoms

Rhonda M Cooper-DeHoff et al. Clin Pharmacol Ther. 2022 May.

. 2022 May;111(5):1007-1021.

doi: 10.1002/cpt.2557. Epub 2022 Mar 11.

Authors

Affiliations

¹ Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics and Precision Medicine, College of Pharmacy, University of Florida, Gainesville, Florida, USA.
² Division of Cardiovascular Medicine, Department of Medicine, College of Medicine, University of Florida, Gainesville, Florida, USA.
³ Department of Clinical Pharmacology, Individualized Drug Therapy Research Program, University of Helsinki, Helsinki, Finland.
⁴ HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland.
⁵ Individualized Drug Therapy Research Program, University of Helsinki, Helsinki, Finland.
⁶ Divisions of Clinical Pharmacology & Research in Patient Services, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
⁷ Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
⁸ Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, Michigan, USA.
⁹ Department of Experimental and Clinical Pharmacology, University of Minnesota College of Pharmacy, Minneapolis, Minnesota, USA.
¹⁰ Department of Biomedical Data Science, School of Medicine, Stanford University, Stanford, California, USA.
¹¹ Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
¹² Department of Internal Medicine, University of South Dakota Sanford School of Medicine, Sioux Falls, South Dakota, USA.
¹³ Department of Medical Sciences, Clinical Pharmacogenomics & Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
¹⁴ Division of Cardiovascular Medicine and Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
¹⁵ Department of Pharmacology and Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
¹⁶ Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, USA.
¹⁷ Departments of Pediatrics and Medicine, University of California, San Francisco, California, USA.
¹⁸ The Wolfson Centre for Personalised Medicine, University of Liverpool, Liverpool, UK.
¹⁹ Division of Primary Care and Population Health, Stanford University School of Medicine, Stanford, California, USA.
²⁰ Division of Clinical Pharmacology, Toxicology, and Therapeutic Innovation, Children's Mercy Kansas City and School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri, USA.
²¹ Division of Pharmaceutical Sciences, Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
²² Department of Medicine, Duke Center for Applied Genomics & Precision Medicine, Duke University School of Medicine, Durham, North Carolina, USA.

PMID: 35152405
PMCID: PMC9035072
DOI: 10.1002/cpt.2557

Abstract

Statins reduce cholesterol, prevent cardiovascular disease, and are among the most commonly prescribed medications in the world. Statin-associated musculoskeletal symptoms (SAMS) impact statin adherence and ultimately can impede the long-term effectiveness of statin therapy. There are several identified pharmacogenetic variants that impact statin disposition and adverse events during statin therapy. SLCO1B1 encodes a transporter (SLCO1B1; alternative names include OATP1B1 or OATP-C) that facilitates the hepatic uptake of all statins. ABCG2 encodes an efflux transporter (BCRP) that modulates the absorption and disposition of rosuvastatin. CYP2C9 encodes a phase I drug metabolizing enzyme responsible for the oxidation of some statins. Genetic variation in each of these genes alters systemic exposure to statins (i.e., simvastatin, rosuvastatin, pravastatin, pitavastatin, atorvastatin, fluvastatin, lovastatin), which can increase the risk for SAMS. We summarize the literature supporting these associations and provide therapeutic recommendations for statins based on SLCO1B1, ABCG2, and CYP2C9 genotype with the goal of improving the overall safety, adherence, and effectiveness of statin therapy. This document replaces the 2012 and 2014 Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for SLCO1B1 and simvastatin-induced myopathy.

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Conflict of interest statement

CONFLICTS OF INTEREST

THE AUTHORS DECLARED NO COMPETING INTERESTS FOR THIS WORK.

Figures

**FIGURE 1.**
SLCO1B1 recommendations with intensity and statin dose stratified by SLCO1B1 phenotype; all doses assume adult dosing.

See this image and copyright information in PMC

References

1. Wilke RA et al. The clinical pharmacogenomics implementation consortium: CPIC guideline for SLCO1B1 and simvastatin-induced myopathy. Clin Pharmacol Ther 92, 112–7 (2012). - PMC - PubMed
1. Ramsey LB et al. The clinical pharmacogenetics implementation consortium guideline for SLCO1B1 and simvastatin-induced myopathy: 2014 update. Clin Pharmacol Ther 96, 423–8 (2014). - PMC - PubMed
1. Grundy SM et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 73, 3168–209 (2019). - PubMed
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1. Turner RM & Pirmohamed M Statin-Related Myotoxicity: A Comprehensive Review of Pharmacokinetic, Pharmacogenomic and Muscle Components. J Clin Med 9, (2019). - PMC - PubMed

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The Clinical Pharmacogenetics Implementation Consortium Guideline for SLCO1B1, ABCG2, and CYP2C9 genotypes and Statin-Associated Musculoskeletal Symptoms

Affiliations

The Clinical Pharmacogenetics Implementation Consortium Guideline for SLCO1B1, ABCG2, and CYP2C9 genotypes and Statin-Associated Musculoskeletal Symptoms

Authors

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Abstract

Conflict of interest statement

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